Second multistate outbreak of tuberculosis caused by a bone allograft product

This paper reports a second multistate tuberculosis outbreak linked to a bone allograft product, highlighting critical gaps in current donor screening and tissue testing protocols that failed to detect *Mycobacterium tuberculosis* until after the outbreak occurred, resulting in significant morbidity and mortality among recipients.

The Gist

Imagine the human body as a house that sometimes needs repairs. When a wall is damaged, doctors might use a "patch" made from another person's bone to help the repair. This patch is called a bone allograft. Usually, these patches are safe, but in this story, a specific batch of bone patches turned out to be dangerous because they were hiding a silent, invisible enemy: tuberculosis (TB).

Here is the story of what happened, explained simply:

The Invisible Stowaway

In 2023, a man in his 70s passed away. Before he died, he was sick with pneumonia and confusion, but doctors didn't realize he also had active tuberculosis. Because the TB wasn't caught, his bones were harvested to make those "patches" for other people.

Think of the bone bank like a bakery. Usually, they check the ingredients to make sure no one is sick. But in this case, the "baker" (the tissue recovery team) didn't know the "flour" (the donor's bones) was contaminated. They made 50 units of bone product and shipped them to hospitals and dental offices across nine different states.

The Outbreak Unfolds

Once these bone patches were implanted into 36 people (mostly for back surgeries, some for dental work), the hidden TB bacteria started to wake up.

• The Infection: Out of the 36 people who received the bone, 27 of them caught the TB infection. It's like planting a seed that grows into a weed inside their bodies.
• The Disease: For 11 of those people, the infection grew strong enough to make them actually sick. The bacteria attacked their spines, lungs, and even their brains.
• The Tragedy: Sadly, three people died from the TB. Two died within a year of the surgery, and a third person died nearly three years later. This third person had stopped taking their medicine early, and when their immune system was weakened later, the TB came back with a vengeance.

The Detective Work

When doctors in different states started seeing patients with strange infections after back surgery, they realized something was wrong. It was like a few different towns noticing the same strange illness and realizing they all bought food from the same bad supplier.

The CDC (the national health detectives) and the FDA stepped in. They traced the problem back to that one specific batch of bone.

• The Test Failure: When they tested the bone before it was shipped, a high-tech "sniffer" test (PCR) didn't find the TB. It was like trying to find a single needle in a haystack with a metal detector that wasn't sensitive enough.
• The Real Discovery: They only found the TB when they grew the bacteria in a lab dish (culture) after the outbreak was already happening. Even then, they only found it in 2 out of 6 leftover bone units. This means the bacteria were there, but they were hiding so well that standard tests missed them.

Why This Matters

This paper tells us that even with all our modern technology, we still have gaps in our safety net.

1. Donors aren't always screened perfectly: The man who donated the bones had symptoms of TB (cough, weight loss, confusion), but no one connected the dots before his bones were used.
2. Tests aren't magic: The standard tests used at the time couldn't guarantee the bone was free of TB, especially because the bone was processed to keep cells "alive," which makes it harder to sterilize without killing the cells.
3. Doctors need to be watchful: The outbreak was only stopped because doctors paid attention. They saw the pattern, reported it, and stopped the use of the bad bone.

The Lesson

The paper concludes that while we can try to pick healthier donors and test the bones better, we might never be 100% sure a bone patch is free of TB. Therefore, the most important thing is for doctors to keep a close eye on anyone who gets a bone transplant. If something looks wrong, they need to speak up immediately so the "bad batch" can be pulled off the shelf before it hurts more people.

In short: A hidden sickness in a donor led to a nationwide scare. Standard tests missed it, but careful doctors caught it in time to save many lives, though not all. It's a reminder that in medicine, sometimes the best safety net is a vigilant human eye.

Technical Summary

Technical Summary: Second Multistate Outbreak of Tuberculosis Caused by a Bone Allograft Product

Problem Statement
Tuberculosis (TB) screening is not mandatory for prospective tissue donors, creating a vulnerability in the safety of allograft products. This paper addresses a critical public health failure: a second nationwide outbreak of Mycobacterium tuberculosis transmission linked to a bone allograft product in 2023. This event followed a similar 2021 outbreak, indicating persistent gaps in donor selection and tissue testing protocols. The specific problem investigated was the morbidity, mortality, and transmission dynamics among recipients of a contaminated, cryopreserved, live-cell bone matrix product derived from a deceased donor with unrecognized active TB.

Methodology
The study employed a prospective cohort design and a comprehensive public health investigation:

• Cohort Identification: The Centers for Disease Control and Prevention (CDC) collaborated with the tissue manufacturer and health departments to identify all 36 recipients of the affected product lot (49 implanted units) across nine states between February and June 2023.
• Clinical Assessment: A prospective cohort study was conducted from July 2023 to July 2024. Standardized case report forms were used to collect demographic, clinical, laboratory, and imaging data. Recipients were classified based on microbiologic confirmation (culture or nucleic acid amplification testing) or imaging evidence of TB disease.
• Pathology and Genomics: Postmortem examinations were performed on one deceased recipient, including immunohistochemical staining and PCR. Whole-genome sequencing (WGS) and multilocus sequence typing were conducted on M. tuberculosis isolates from four recipients and two unused product units to establish genetic relatedness.
• Donor and Product Investigation: The donor's medical history, risk assessment interview, and terminal hospitalization records were reviewed. Unused product units were tested using real-time PCR and mycobacterial culture (liquid and solid media).

Key Results

• Transmission and Infection: Of the 36 recipients, 27 (77%) developed M. tuberculosis infection (positive interferon-gamma release assay). Eleven recipients (31%) developed active TB disease, with a median time to diagnosis of 72 days post-implantation.
• Clinical Manifestations: Disease sites included the spine/paraspinal soft tissues (9 cases), lungs (4), central nervous system (2), and lymph nodes (1). Spinal imaging frequently revealed abscesses, fluid collections, osteomyelitis, or discitis.
• Morbidity and Mortality: Two recipients died within 12 months of outbreak detection (70 and 113 days post-surgery), with TB listed as the cause of death. A third recipient died in 2025, nearly three years after implantation, following the cessation of treatment and initiation of immunosuppressive therapy.
• Treatment Outcomes: All 36 recipients initiated empiric multidrug therapy. While 32 completed therapy, two stopped early. Four recipients required additional surgical interventions, including allograft removal.
• Donor and Product Analysis: The donor, a man in his 70s, died of pneumonia and septic shock with no documented TB testing prior to death. He exhibited symptoms consistent with TB (chronic cough, weight loss, fever).
  • Testing Discrepancy: PCR testing of the product before and after distribution was consistently negative for M. tuberculosis.
  • Culture Findings: M. tuberculosis was isolated via culture from only 2 of 6 unused product units tested after the outbreak was detected.
  • Genomic Evidence: WGS confirmed that isolates from recipients and unused units shared a unique sequence type, differing by 0–2 single nucleotide polymorphisms, confirming a common source.

Key Contributions

• Documentation of a Second Outbreak: The paper provides the first comprehensive description of morbidity and mortality for the second multistate TB outbreak linked to bone allografts, highlighting that such events are not isolated incidents.
• Limitations of Current Screening: The study demonstrates that PCR testing of tissue products may yield false negatives due to low bacterial load, and that standard donor risk assessments can fail to identify active TB in donors with non-specific symptoms (e.g., sepsis of unknown etiology).
• Genomic Confirmation: The use of whole-genome sequencing definitively linked the donor, the unused product, and the recipients, confirming the transmission pathway despite negative initial PCR results.
• Delayed Mortality: The case of the recipient dying nearly three years post-implantation underscores the long latency and potential for delayed fatal outcomes if treatment is interrupted or if the recipient becomes immunocompromised.

Significance and Claims
The authors claim that this outbreak highlights persistent deficiencies in the safety of tissue transplantation in the United States. Specifically, they assert that:

1. Donor Selection Gaps: Adherence to FDA policies prohibiting tissue recovery from donors with sepsis would have prevented this outbreak, as the donor presented with sepsis and pneumonia consistent with TB.
2. Testing Limitations: While mycobacterial culture of donated tissues could reduce risk, it cannot eliminate it, as evidenced by the fact that only 2 of 6 unused units cultured positive. Furthermore, the processing of live-cell products precludes sterilization methods that would kill the pathogen.
3. Clinical Vigilance: The detection of this outbreak relied on clinicians recognizing similarities to the 2021 event and reporting adverse events. The authors emphasize that reporting remains voluntary and that clinicians must actively monitor recipients and report adverse events to tissue establishments and health authorities.
4. Systemic Recommendations: The paper supports recommendations for improved informed consent regarding communicable disease risks and the development of electronic biovigilance systems to ensure traceability and systematic reporting of adverse events.

The study concludes that while improved donor selection and pre-distribution culture testing could reduce transmission risk, they are insufficient to eliminate it entirely, necessitating a robust system of post-transplant surveillance and rapid reporting.